Immunotoxins: Future Advances and Directions

Dear Colleagues,

Immunotoxins (ITs) are hybrid protein molecules comprised of an antibody component coupled either chemically or fused genetically to a large proteinaceous bacterial or plant-derived toxin molecule such as diphtheria toxin, pseudomonas exotoxin or saporin. Their selective cytotoxicity for target antigen bearing cells is exerted once the toxin component gains access to the target cell cytosol where it irreversibly inhibits protein synthesis, thus bringing about apoptotic cell death. ITs can rightly be considered as the predecessors of today’s antibody drug conjugates (ADC) that are now in rapid clinical development. It is now 48 years since the first IT was described by Moolten and coworkers in 1970 [1] and then developed further by Thorpe and his co-workers [2]. Since then a succession of next generation ITs have been under constant investigation as promising therapeutic entities particularly for haeamatological malignancies [3]. During this time they have been repeatedly shown to possess significant selective cytotoxicity for target cells bearing the target antigen and furthermore have, in some cases, exhibited significant activity against a range of cancers in clinical trials. The question therefore is why have IT’s largely failed to capture the attention of the pharmaceutical industry whereas ADC’s have succeeded in doing so?

The series of papers presented in this special edition of Biomedicines on immunotoxins will critically examine the major issues that have ostensibly prevented the widespread commercial clinical development of ITs. Each paper will examine a particular practical problem and offer a solution to this with a view to improving the therapeutic efficacy and safety of IT therapy. Amongst the subject areas covered will be the importance of single versus multiple antigen targeting, target antigen internalization and trafficking, the problem of immunogenicity, off-target toxicities, and a variety of other strategies that could be brought to bear to improve the overall therapeutic index of ITs. The matter of manufacturing methods for recombinant ITs will also be covered with an eye on the practicalities for the large scale manufacture of clinical grade IT.  All these aspects of pre- clinical IT development will be presented in the context of past clinical studies that have brought to our attention the problems that have limited the full clinical development of ITs. It is to be hoped that the solutions on offer through these series of papers will reinvigorate the field once it is clear that previously encountered problems are indeed surmountable. This we hope will provide a sound rationale that will argues for the continued clinical development of ITs for a variety of human malignancies.

We cordially invite authors working in this field to submit original research or review articles that are relevant to the stated objectives of this special edition of Biomedicines on immunotoxins.

The guest editors would like to dedicate this special edition of Biomedicines on Immunotoxins to the memory of Dr Philip E. Thorpe (1951 – 2013) for his seminal contributions over many years to the immunotoxin field.

1. Moolten, F.L.; Cooperband, S.R. Selective destruction of target cells by diphtheria toxin conjugated to antibody directed against antigens on the cells. Science 1970, 169, 68-70.
2. Thorpe, P.E.; Ross, W.C.; Cumber, A.J.; Hinson, C.A.; Edwards, D.C.; Davies, A.J. Toxicity of diphtheria toxin for lymphoblastoid cells is increased by conjugation to antilymphocytic globulin. Nature 1978, 271, 752-755.
3. Wayne, A.S.; Fitzgerald, D.J.; Kreitman, R.J.; Pastan, I. Immunotoxins for leukemia. Blood 2014, 123, 2470-2477.

Dr. David J Flavell
Guest Editor

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• Immunotoxins
• therapy
• cancer
• augmentation
• therapeutic index
• immunogenicity
• target antigens
• clinical trials
• clinical grade drug manufacture.